This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Food Protein-Induced Enterocolitis Syndrome (FPIES) is a severe infantile cell-mediated, non-IgE antibody-associated food hypersensitivity caused typically by cow's milk and/or soy (1-6) FPIES is characterized by profuse vomiting and diarrhea, with progression to dehydration and shock in 20% of patients. Inital reports described young infants with these symptoms following ingestion of cow's milk or soy-based formula. Patients rapidly recover with milk- and soy-free diets, but ingestion of these proteins following a period of dietary elimination triggers subacute symptoms over 2-3 hours following ingestion with an associated elevation of the peripheral blood polymorphonuclear leukocyte count. Although there are case reports of rice and other foods causing FPIES, solid food proteins are not well recognized as potential triggers of FPIES. However, in our clinical practice we have observed infants with FPIES due to dietary food proteins other than cow's milk and/or soy, including several foods (oat, barley, squash, sweet potato) never before reported to cause this disorder. We propose to investigate FPIES to better characterize the natural history of this syndrome, characterize pathophysiology of the immune responses to food allergens, and to determine the markers of tolerance. FPIES is a severe syndrome of vomiting and diarrhea typically caused by cow's milk or soy protein in infants younger than 9 months. Approximately half of affected infants react to both milk and soy proteins. Some patients present with dramatic symptoms of profuse vomiting, with or without diarrhea, which may progress to acidemia and shock. Associated methemoglobinemia is thought to result from increased heme oxidation caused by an elevation of nitrates in the intestine. Biopsies show crypt abscesses, diffuse inflammatory cell infiltrates with plasma cells in the colon, and edema with mild villous injury in the small intestine. The diagnosis is typically made on the basis of clinical criteria and, if necessary, by a standardized oral challenge protocol. The disorder is cell-mediated and occurs typically without positive allergy prick skin tests or serum allergen-specific IgE antibodies. Recent studies suggest that FPIES is predominantly mediated by T cells, which have been shown to secrete TNF-alpha upon milk stimulation. A relative lack of expression of transforming growth factor - beta (TGF-beta) may also be involved. Within 2 years, 60% of milk and 20% of soy-induced FPIES resolves. Solid food proteins are not recognized potential culprits but reports from the literature as well as our clinical experience indicate that grains, meats, fruits and vegetables are capable of inducing FPIES. Although the prevalence of FPIES is unknown, considering increasing prevalence of other food hypersensitivity syndromes, a rise in FPIES may be expected. Therefore it is important to characterize the natural history of this disorder for more efficient managements of the patients. We propose to prospectively study FPIES in children to determine the average age of achieving tolerance as well as mechanisms involved in tolerance development.